SPID#: 30 High-dose chemotherapy and marrow-lethal chemotherapy with marrow or peripheral blood stem cell support are effective, potentially curative treatment modalities for patients with a variety of malignancies. The principal short term adverse effect of such aggressive treatment is severe pancytopenia with consequent immediate susceptibility to infection and bleeding, often requiring antibiotics and platelet transfusion support. A long term adverse effect of such therapies is the development of "stem cell exhaustion" characterized by the development of chronic pancytopenias and extreme sensitivity of the hematopoietic system to the suppressive effects of further conventional dose chemotherapy. Animal models of high-dose chemotherapy that produce reversible marrow injury, and that produce marrow-lethal chemotherapy requiring hematopoietic stem cell rescue will be essential in developing new strategies to lessen these short-term and long-term adverse effects. These new strategies, for example, will involve the use of recently cloned recombinant hematopoietic growth factors to accelerate post-chemotherapy marrow regeneration, and to facilitate the collection of marrow regenerating cells for use in stem cell rescue. In addition, the marrow lethal model requiring stem cell rescue will be an essential tool in investigations of stem cell purification techniques and use of genetically altered stem cells for gene therapy. Previously we have developed a chemotherapy induced marrow injury model employing hepsulfam. This drug will probably not remain available, however intravenous busulfan has just recently been developed and was used in phase I human clinical trials in 1995. Oral busulfan is the major drug in many high dose chemotherapy protocols requiring cell rescue. Intravenous busulfan will probably eventually replace the oral form of the drug in these protocols. In 1995 we conducted dose escalation studies using intravenous busulfan, and have established a marrow damaging dose from which the hematopoietic system can regenerate from surviving endogenous stem cells, and a marrow lethal dose that requires post-chemotherapy stem cell rescue. Using this latter dose, we have performed autologous stem cell rescue in several animals. This new intravenous busulfan autologous stem cell model will be valuable for studies to determine the effect on hematopoietic regeneration of various cytokines administered during the post-transplant period.